Abdominal pain and abnormal bowel habits represent major symptoms for irritable bowel syndrome (IBS) patients that are not adequately managed. Although the etiology of IBS is not completely understood, many of the functions of the gastrointestinal (GI) tract are regulated by the enteric nervous system (ENS). Inflammation or stress-induced expression of growth factors or cytokines may lead to hyperinnervation of visceral afferent neurons in GI tract and contribute to the pathophysiology of IBS. Rearranged during transfection (RET) is a neuronal growth factor receptor tyrosine kinase critical for the development of the ENS as exemplified by Hirschsprung patients who carry RET loss-of-function mutations and lack normal colonic innervation leading to colonic obstruction. Similarly, RET signaling in the adult ENS maintains neuronal function by contributing to synaptic formation, signal transmission, and neuronal plasticity. Inhibition of RET in the ENS represents a novel therapeutic strategy for the normalization of neuronal function and the symptoms of IBS patients. Herein, we describe our screening effort and subsequent structure-activity relationships (SARs) in optimizing potency, selectivity, and mutagenicity of the series, which led to the discovery of a first-in-class, gut-restricted RET kinase inhibitor, 2-(4-(4-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)--(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)acetamide (, GSK3179106), as a clinical candidate for the treatment of IBS. GSK3179106 is a potent, selective, and gut-restricted pyridone hinge binder small molecule RET kinase inhibitor with a RET IC of 0.3 nM and is efficacious .
We demonstrate theoretically a 2D subwavelength silicon-grating reflector with strong focusing capability and the potential application to an optical dipole trap of cold molecules such as MgF. We study the dependence of the focusing properties of this reflector on its structural parameters, numerical aperture, and fabrication-error tolerance. Our study shows that the reflector delivers high reflectivity and strong focusing performances with the maximum intensity at the focal point over 200 times the incident one. Such a focusing field on the reflector can provide a deep potential to trap cold MgF molecules from a standard magneto-optical trap.
We propose a tightly focused hollow beam to trap cold molecules by using a metasurface grating, which has a hybrid phase with focusing and completely destructive interference functions. The intensity distributions of the hollow beam in free space concerning different structural parameters of the grating are theoretically studied in detail. The influences of both the discrete and continuous phases of the grating on the intensity distribution of the modulated optical field are compared. Our theoretical study shows that such a blue-detuned beam can provide a deep potential to trap cold molecules with a low photon scattering rate and a long trap lifetime. Our studies suggest that the metasurface-based optical chip is applicable to trap molecules and can be an ideal platform for building a robust quantum laboratory.
Alzheimer’s disease (AD) and vascular dementia (VD) are the two most common forms of dementia, share similar symptoms, and are sometimes difficult to distinguish. To investigate the potential mechanisms by which they differ, we identified differentially expressed genes in blood and brain samples from patients with these diseases, and performed weighted gene co-expression network analysis and other bioinformatics analyses. Weighted gene co-expression network analysis resulted in mining of different modules based on differences in gene expression between these two diseases. Enrichment analysis and generation of a protein-protein interaction network were used to identify core pathways for each disease. Modules were significantly involved in cAMP and AMPK signaling pathway, which may be regulated cell death in AD and VD. Genes of cAMP and neurotrophin signaling pathways, including ATP1A3, PP2A, NCEH1, ITPR1, CAMKK2, and HDAC1, were identified as key markers. Using the least absolute shrinkage and selection operator method, a diagnostic model for AD and VD was generated and verified through analysis of gene expression in blood of patients. Furthermore, single sample gene set enrichment analysis was used to characterize immune cell infiltration into brain tissue. That results showed that infiltration of DCs and pDCs cells was increased, and infiltration of B cells and TFH cells was decreased in the brain tissues of patients with AD and VD. In summary, classification based on target genes showed good diagnostic efficiency, and filled the gap in the diagnostic field or optimizes the existing diagnostic model, which could be used to distinguish between AD and VD.
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